tbuckley/cabot-search huggingface dataset:
Abstract P2138: Long-Term Clinical Value And Impact Of Mavacamten In Symptomatic Obstructive Hypertrophic Cardiomyopathy: A Systematic Review And Meta-Analysis
Authors: Sneha Annie Sebastian, Ubaid Khan, Inderbir Padda, Arun Mahtani, Muhammad M Nasir, Muhammad Mubariz, Javed Iqbal, Gurpreet Johal
Journal: Circulation Research (2023)

Introduction: Hypertrophic cardiomyopathy (HCM) is a common genetic cardiac disorder involving the cardiac sarcomere. Mavacamten is the first-in-class oral cardiac myosin inhibitor approved for treating HCM in adults targeting sarcomere hypercontractility. We aimed to evaluate the efficacy and safety of mavacamten in symptomatic obstructive HCM. Methods: We conducted a systematic literature search in Embase, PubMed, Scopus, and Web of Science databases from inception until March 05, 2023. Results: After screening 349 studies, our final analysis included 5 studies with 843 obstructive HCM patients and an average follow-up of 27.2 weeks. A fixed effects model was used to calculate risk ratios (RRs). Our meta-analysis revealed a significant improvement in NYHA functional class from baseline in patients on mavacamten compared to placebo [RR, 4.59 (95% CI: 2.94-7.16), p&lt;0.00001]. Mavacamten use in obstructive HCM patients also resulted in significantly lower rates of septal reduction therapy (SRT) or patients who were guideline-eligible for SRT versus placebo [RR, 0.29 (95% CI: 0.22-0.39), p&lt;0.00001]. There was no significant effect of mavacamten use on the Kansas City Cardiomyopathy Questionnaire (KCCQ) score (p = 0.22). Also, no significant difference was observed in the occurrence of ≥1 serious adverse event (p = 0.77), atrial fibrillation (p = 0.98), and non-sustained ventricular tachycardia (p = 0.44) between mavacamten and placebo group. Conclusions: A substantial improvement in NYHA functional class without any serious adverse events, and a significant reduction in the number of patients requiring SRT, makes mavacamten a promising drug for obstructive HCM.
Abstract P1163: Identifying Novel Intracellular Interactions Driving Membrane-bound Tumour Necrosis Factor-mediated Signalling In The Microvasculature
Authors: Yasaman Mostafaie, Julia Hanchard, Darcy Lidington, Steffen-Sebastian Bolz
Journal: Circulation Research (2023)

Elevated total peripheral resistance (TPR) is a hallmark of many cardiovascular diseases and furthers disease progression. We previously demonstrated that myogenic tone, regulated by membrane-bound tumour necrosis factor (mTNF) reverse signalling, is a primary modulator of TPR. Thus, inhibiting mTNF reverse signalling should reduce TPR with the potential to improve disease outcome. However, since mTNF is a ubiquitous protein with critical biological functions, its indiscriminate inhibition can cause widespread side effects. Therefore, therapeutics aiming to reduce myogenic tone and TPR must target other elements of mTNF reverse signalling. To identify these unknown participants of mTNF reverse signalling, we used proximity-dependent biotinylation coupled to mass spectrometry (BioID). Our search identified 42 high confidence hits that interact with and/or are proximal to mTNF’s cytoplasmic domain. Gene ontology (GO) analysis revealed that molecularly, these proteins are structural constituents of the cytoskeleton involved in actin and cell adhesion molecule binding. This aligns with our underlying hypothesis that mTNF functions as a mechanosensor that tethers to its receptors and initiates myogenic vasoconstriction in response to changes in transmural pressure. GO also identified proteins involved in MAPK and RhoA signalling, which are critically involved in myogenic vasoconstriction. Our most abundant hit (fold change = 12.6, p-value = 0.0023) is a cytoskeletal protein that plays a role in maintaining the structural integrity of cells. This protein also interacts with proteins involved in various signalling cascades, namely, RhoA and calcium-dependent signalling pathways. Thus, we hypothesize that this protein is essential for formation of signalling complexes with mTNF and interacts with other proteins to mediate reverse signalling . We will employ a bioluminescence-based approach to quantify the strength of all interactions detected by BioID and identify small molecule inhibitors that can disrupt these interactions. These newly discovered inhibitors could potentially be used as novel therapeutics targeting myogenic tone and hence, elevated TPR to improve disease management and clinical outcome of cardiovascular diseases.
Abstract P2165: Endothelial Leptin Resistance Exacerbates Vascular Dysfunction Through Attenuating PD-L1 Expression
Authors: Yiu Ming Cheung, Wing Tak Wong
Journal: Circulation Research (2023)

Background: Obesity and its vascular complications are escalating globally that threaten millions of people and incurring tremendous financial costs. Fundamentally, endothelial dysfunction is the culprit among these cardiovascular diseases due to the presence of risk factors such as hyperglycemia and hyperlipidemia, which enhance the inflammatory responses and leucocyte infiltration. Persistent endotheliopathy is closely associated to severe cardiovascular events, ultimately leading to mortality. Leptin is a pleiotropic adipokine that is significantly expressed in obese people, resulting in leptin resistance. Programmed cell death ligand 1 (PD-L1; encoded by gene Cd274 ) is the inhibitory immune checkpoint that limits immunogenic responses of lymphocytes by causing functional exhaustion and apoptosis in lymphocytes. The relationship between endothelial PD-L1 expression and progression of vasculopathy has not yet been elucidated. Methods: Providing that circulating leptin level is closely associated with body adiposity and feeding behaviors, both hypoleptinemia and hyperleptinemia were generated on C57BL/6 mice by nutritional modulation or genetic knockout on leptin receptor. Results: Findings across multiple models suggested, the expression of PD-L1, an immune-coinhibitory molecule, was regulated by leptin, the impairment in leptin signaling resulted in vascular PD-L1 downregulation. By employing the mice with obesogenic hyperleptinemia, we showed that the vascular tissue failed to respond to exogenous leptin stimuli, thereby hindering PD-L1 expression in the inflammatory microenvironment. In fact, PD-L1 expression is crucial in maintaining tissue homeostasis by suppressing the activated PD-1 + leukocytes, as such hindered PD-L1 expression may favor the vascular inflammation by failing to inhibit immunogenic attack, especially when other risk factors are present. Beyond acting as a ligand to leukocytes, our findings also revealed PD-L1 reverse signaling in endothelium plays a role in resolving inflammation and rescuing endothelial function. Summary: These findings propose a new explanation for why obesity results in vasculopathy in relationship with PD-L1.
Abstract P3115: Disruption Of Assembly By Estrogen Limits Microtubule Proliferation In Failing Heart Cells
Authors: Allison Ogren, Simone Stark, Mark McClellan, Lynn Hartweck, Kurt W Prins, Melissa Gardner
Journal: Circulation Research (2023)

Right heart failure, resulting from high pressure in the pulmonary artery, is the leading cause of mortality in pulmonary arterial hypertension (PAH). Interestingly, females with PAH have superior right ventricular (RV) function, which can mostly explain improved survival in female patients. Microtubules are long filaments that regulate cellular contractility and transport within cardiac cells. The excess proliferation of microtubules is associated with pathological t-tubule remodeling in failing RV cardiomyocytes. Previous work suggests that the female hormone estrogen disrupts microtubule assembly. Here, we explored whether estrogen treatment could ameliorate the pathological proliferation of microtubules. By utilizing iPSC-derived cardiomyocytes with live-cell confocal imaging, we show that estrogen treatment leads to long pausing during microtubule growth, like the microtubule inhibitor colchicine. Additionally, estrogen treatment rescues microtubule overgrowth in endothelin-stressed primary cardiomyocytes (Fig. 1). We examined the molecular mechanism using purified tubulin, the building block of microtubules, and estrogen. In cell-free experiments, estrogen induced long pauses in microtubule growth. Our preliminary data suggest that estrogen, like colchicine, binds to free tubulin and co-polymerizes with it, disrupting microtubule assembly independent of estrogen receptors. We conclude that estrogen’s ability to limit microtubule proliferation could contribute to sex differences in RV function in PAH. Figure 1: Primary cardiomyocytes. Microtubule proliferation in endothelin-treated cells was rescued with estradiol.
Abstract P3135: <i>In Vivo</i> Dissection Of CaMKII-Mediated Arrhythmias In CPVT
Authors: Nikoleta Pavlaki, Sofia de la Serna Buzon, Mason Sweat, William T Pu, Steven Marx, Vassilios J Bezzerides
Journal: Circulation Research (2023)

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome of the structurally intact heart manifesting life-threatening bursts of ventricular tachycardias due to dominant gain-of-function mutations in the ryanodine receptor type 2 (RyR2) and β-adrenergic (β-AR) stimulation. Both protein kinase A (PKA) and Ca 2+ - calmodulin-dependent protein kinase II (CaMKII) can phosphorylate RyR2 channels, but only the latter can initiate the arrhythmogenic phenotype in CPVT. Whether through L-type Ca 2+ channel (LTCC)-mediated Ca 2+ increase or the Epac2-nitric oxide pathway, the exact mechanism by which β-AR-mediated CaMKII activation unmasks lethal arrhythmias in CPVT remains unresolved. Aim: To gain mechanistic insight and ablate ventricular arrhythmias in a mouse model of CPVT by selectively disrupting integral components of β-AR signaling. Methods: By utilizing either direct adeno-associated virus (AAV) delivery or the CRISPR/Cas9-AAV-based somatic mutagenesis (CASAAV) system, we selectively expressed a mutant LTCC β 2 -subunit, ablated the small GTPase Rad, or disrupted other components of the β-AR pathway in the hearts of mice with the pathogenic RyR2 mutation R4650I as a model of CPVT. The effects of disruption of LTCC regulation were determined by high-speed Ca 2+ imaging of isolated ventricular cardiomyocytes or whole animal electrophysiological (EP) testing for ventricular arrhythmia incidence in vivo . Results &amp; Conclusions: Our data demonstrate that abnormal RyR2-mediated calcium release events are induced by hyperactivated LTCCs in vitro , even in the absence of adrenergic stimulation, with increased arrhythmia incidence in vivo . These results suggest that β-AR stimulation leads to pathogenic RyR2 Ca 2+ leak through LTCC-mediated contribution to CaMKII hyperactivity. Alternative mechanisms of CaMKII activation that mediate arrhythmia induction in CPVT require additional future investigation.
Abstract P1049: The Impact Of Endurance Exercise On Longer-term Myocardial Fibrosis Development And Ventricular Arrhythmogenicity In Murine Coxsackievirus B3 Myocarditis
Authors: Kasper Favere, Manon Van Hecke, Sander Eens, Matthias Bosman, Peter L Delputte, Johan De Sutter, Erik Fransen, Tania Roskams, Pieter-Jan Guns, Hein Heidbuchel
Journal: Circulation Research (2023)

Aims: Diagnostic work-up of athletes often reveals nonischaemic myocardial fibrosis, which is associated with cardiac dysfunction and malignant arrhythmias. Its isolated finding on magnetic resonance imaging is commonly attributed to preceding viral myocarditis. Previous murine studies have shown a negative effect of exercise early in the course of viral myocarditis. In this study, we investigate, for the first time, the impact of endurance exercise on myocardial fibrosis development and arrhythmogenicity in a murine viral myocarditis model. Methods &amp; Results: Eleven-week-old male C57BL/6J mice (n=72) were randomised to 8 weeks of treadmill running (EEX) or without exercise (SED). After 2 weeks, animals received a single injection with either coxsackievirus B3 to induce acute viral myocarditis (CVB) or vehicle as control (PBS). Exercise resulted in a milder clinical disease course, with less weight loss and better preserved running capacity. In addition, mortality was lower in exercising myocarditis mice (11 vs. 27%), however without statistical significance (P=0.23). Exercise during myocarditis increased the occurrence of interstitial fibrosis (limited or extensive distribution) at sacrifice ( i.e. 6 weeks after inoculation)(82.4% in CVB-EEX vs. 56.3% in CVB-SED; P=0.049). Additionally, exercise enhanced development of perivascular and/or interstitial fibrosis with extensive distribution (64.7% &amp; 64.7% in CVB-EEX vs. 50% &amp; 31.3% in CVB-SED; P=0.048). CVB-EEX animals demonstrated more myocardial scars on average, albeit not significantly (1.9 vs. 1.2; P=0.19), with similar scar distribution. Despite manifest fibrotic remodelling, collagen and fibrogenetic genes were not upregulated in the myocarditis groups at the time of sacrifice. In vivo right ventricular programmed electrical stimulation showed comparable ventricular arrhythmia inducibility in the myocarditis groups (P&gt;0.20). The longest arrhythmias and highest cumulative arrhythmia burden occurred in CVB-EEX, however, without reaching statistical significance when compared to CVB-SED (P=0.49). Conclusion: Endurance exercise during viral myocarditis enhances perivascular and interstitial fibrosis development, which may promote ventricular arrhythmogenicity.
Abstract P1162: Nedd4-2 Inactivation Underlies The Increase In Cardiac Sodium-dependent Glucose Cotransporter-1 In Diabetic Hearts
Authors: Vivek K Pandey, Sathya Velmurugan, Sanda Despa
Journal: Circulation Research (2023)

Rationale: Type-2 diabetes (T2D) is a major risk factor for developing heart failure. While the underlying mechanisms are poorly understood, recent evidence suggests that upregulation of the Na + /glucose cotransporter 1 (SGLT1) plays an important role, as it causes myocyte Na + overload. Objective: To identify the mechanisms involved in promoting an increase in SGLT1 protein level in diabetic hearts. Methods/Results: We compared hearts from patients with and without T2D and hearts from rats with late-onset T2D caused by overexpression of human amylin in pancreatic β-cells versus hearts from wild-type littermates. SGLT1 protein level was significantly higher in hearts from both humans and rats with T2D. In contrast, the SGLT1 mRNA levels were comparable in hearts from T2D and non-diabetic patients and rats. This result suggests that theT2D-induced increase in cardiac SGLT1 protein occurs at a post-transcriptional level. Co-immunoprecipitation of SGLT1 with ubiquitin was reduced in diabetic human and rat hearts, which indicates that SGLT1 degradation is impaired. The E3 ubiquitin ligase Nedd4-2 is responsible for ubiquitination of several cardiac membrane transporters. Pharmacological inhibition of Nedd4-2 with Heclin in HL-1 cells resulted in significantly higher SGLT1 protein levels, suggesting that Nedd4-2 also mediates SGLT1 degradation. Nedd4-2 is inactivated upon phosphorylation by several kinases, including the serum and glucocorticoid-regulated kinase-1 (SGK1). Using western blotting, we found increased Nedd4-2 phosphorylation in hearts from humans and rats with T2D compared to their non-diabetic counterparts. Moreover, hearts from T2D patients exhibited higher levels of SGK1 and its activated phosphorylated form compared to their non-diabetic counterparts. Conclusion/New Hypothesis: The increase in SGLT1 protein in the diabetic heart is regulated post-transcriptionally by an impairment in Nedd4-2 dependent ubiquitination and degradation of SGLT1.
Abstract P2045: Regulation Of Atrial Natriuretic Peptide Secretion By Palmitoylation And Modulation Of The Rab3a GTPase Cycle In Cardiac Myocytes
Authors: Kobina Essandoh, Arasakumar Subramani, James Teuber, Matthew Brody
Journal: Circulation Research (2023)

Despite the clinical relevance to cardiovascular disease, molecular regulation of atrial natriuretic peptide (ANP) release by cardiomyocytes remains ill-defined. We uncovered novel functions for Rab3gap1 and modulation of Rab3a nucleotide cycling in membrane fusion and atrial natriuretic peptide (ANP) release in cardiomyocytes. We generated transgenic mice overexpressing the Golgi-localized S-acyltransferase, zDHHC9, and identified Rab3gap1 as a novel cardiac substrate of zDHHC9 by S-acyl proteomics. Rab3gap1 palmitoylation and retention at the cardiomyocyte Golgi, Rab3a-GTP levels, and formation of Rab3a-positive post-Golgi vesicles were all enhanced in zDHHC9 overexpressing hearts as were Rab3gap1, Rab3a, and ANP atrial protein levels but circulating ANP levels were reduced, suggesting a defect in ANP secretion. Notably, treatment of cardiomyocytes with the secretagogue phenylephrine (PE) promoted substantial ANP release as expected, but also enhanced Rab3gap1 palmitoylation and Rab3a GTP-loading and peripheral vesicle formation, whereas knockdown of zDHHC9 repressed these PE-induced effects on Rab3gap1 and Rab3a but further enhanced PE-stimulated ANP secretion, suggesting zDHHC9-mediated palmitoylation of Rab3gap1 serves as an intrinsic mechanism to limit ANP release. Consistent with a role for Rab3a nucleotide exchange in modulation of ANP release, overexpression of Rab3gap1 in cardiomyocytes promoted a profound increase in ANP release whereas a GAP-deficient mutant of Rab3gap1 (Rab3gap1 R728A ) was resistant to this effect. Collectively, these data suggest disruption of Rab3a nucleotide cycling perturbs secretory vesicle membrane fusion and ANP release in cardiac myocytes and establish critical roles for Rab3a activity and its modulation by zDHHC9-mediated palmitoylation of Rab3gap1 in governing cardiac homeostasis and endocrine signaling.
Abstract P3105: Stress Exacerbates Ischemia/reperfusion Injury In The Female Heart Through The Glucocorticoid Receptor Signaling In Cardiomyocytes
Authors: Lilly Kamberov, Hemangini Dhaibar, Sonya Patel, Jaylen Pruiett, Xinggui Shen, Wayne W Orr, Steven R Bailey, Christopher Kevil, Robert H Oakley, John A Cidlowski, Diana Cruz-Topete
Journal: Circulation Research (2023)

It is estimated that over 30,000 women younger than 55-years-old die of acute myocardial infarction (AMI) in the United States annually. Clinical data suggest that exposure to mental stress exacerbates the outcomes of an AMI in women. However, a knowledge gap exists regarding the molecular mechanisms whereby stress contributes to AMI in women and how they differ in men. The present project aims to define the mechanisms underlying the link between stress, glucocorticoids (stress hormones), the glucocorticoid receptor (GR) signaling, and the worse outcomes of AMI in females than in their male counterparts. We challenged male and female transgenic mice lacking GR in cardiomyocytes (cardioGRKO) and their respective wild-type controls in a murine model of "mental" stress followed by ischemia/reperfusion (AMI) injury. Our data show that stress exacerbated the response to AMI injury in control females compared to their male counterparts. Females without cardiomyocyte GR were protected and presented significantly reduced infarct areas compared to cardioGRKO males and control males and females with intact GR signaling. These results demonstrated that stress directly affected the heart and that these effects are sexually dimorphic. The severity of the infarct and cardiomyocyte death was further exacerbated during the highest estrogen activity phase (proestrus) of the female cycle. Our in vitro studies additionally supported these data, showing that glucocorticoids block estrogen's pro-survival effects on cardiomyocytes in hypoxia/re-oxygenation conditions in a mechanism dependent upon GR inhibition of estrogen regulation of antioxidant pathways, including decreased levels of the master regulator of the antioxidant response, nuclear factor-erythroid factor 2-related factor 2 (Nrf2), and increased superoxide and lipid peroxides production. Our in vivo models displayed similar findings. Our study is the first to test the impact of mental stress on activating glucocorticoid signaling in the heart in the setting of AMI. This study is relevant to human health as a proof of concept that exposure to high stress levels aggravates AMI in premenopausal hearts by cardiomyocyte GR-regulated mechanisms that may be targeted to develop therapies tailored to women.
Abstract P2136: TpTe Interval Behavior And Mortality In Wistar Rats Submitted To Cardiac Ischemia And Reperfusion Treated With The Heparin Fragment Trisulfated Disaccharide
Authors: Enio R Vasques, Bruna K Vasques
Journal: Circulation Research (2023)

Introduction: The Tp-Te ekg interval reflects ventricular transmural dispersion, being used for prediction of ventricular arrhythmia and sudden death. The heparin fragment called Trisulfated Disaccharide (TD), which has no effect on blood coagulation and acts on the sodium-calcium exchanger accelerating the output of calcium from the cell, decreases cytoplasmic calcium concentrations in situations of calcium overload due to ischemia and reperfusion (I-R). Objective: To evaluate the behavior of the Tp-Te interval and mortality due to cardiac arest in Wistar rats submitted to surgicaly induced I-R under treatment with TD at reperfusion. Materials and Method: Wistar rats (n=8) with average weight of 300g were anesthetized and under assisted breathing were electrocardiographically monitored and submitted to surgical cardiac ischemia by ligation of the anterior descending artery for 10 min, with reperfusion thereafter. The Tp-Te interval was analyzed before ischemia, at 10 min after ischemia induction and at 10 min after reperfusion, The incidence of arrhythmias was determined throughout the recording period. In the study group intravenous (0.2 mg/kg) TD was injected concomitantly with the reperfusion. In the control group (n=8), the same procedure was performed, without the TD infusion. Results: During ischemia there was a similar alteration of the Tp-Te interval in both groups when compared to the pre-ischemic phase, with an increase of about 90% in magnitude, as well as the presence of ventricular arrhythmias, without animal mortality. During reperfusion Tp-Te interval returned to normal in the treated group and there was no mortality. In the control group, the magnitude of the Tp-Te increase was maintained. The presence of ventricular arrhythmias was similar, but total atrioventricular block and/or sustained arrhythmia occurred in 50% of the animals, followed by animals death. Conclusion: Treatment with TD at the time of reperfusion normalized the Tp-Te interval 10 min after TD infusion as well as reduced mortality in wistar rats submitted to I-R, and may be useful in the protection of organs submitted to the same I-R conditions (transplants, surgical and hemodynamic procedures), where calcium overload is determinant in morbidity and mortality.